Voltage-gated calcium channels are formed by combinations of the pore-forming α1 subunit and auxiliary proteins α2δ, β, and γ (Caterall (2000) Annu. Rev. Cell Dev. Biol. 16:521-555). The α2δ protein is known to regulate both calcium channel density and the voltage-dependent kinetics of these channels (Felix et al (1997) J. Neuroscience 17: 6884-6891; Klugbauer et al (1999) J. Neuroscience 19:684-691; Hobom et al (2000) Eur. J. Neuroscience 12:1217-1226; and Qin et al (2002) Mol. Pharmacol. 62:485-496).
Gabapentin (GBP) is an anti-epileptic, anti-hyperalgesic and anxiolytic drug which binds with high affinity to two sub-types of calcium channel α2δ subunits α2δ1 and α2δ2. GBP was originally developed for epilepsy and has also found application in the treatment of pain and anxiety (Taylor et al (1998) Epilepsy Res. 29:223-249). The mechanism underlying GBP's action is still poorly understood. GBP was originally designed as a lipophilic γ-amino butyric acid (GABA) analogue, but has subsequently been shown not to interact with any of the enzymes on the GABA metabolic pathway, nor does it interact directly with the GABAA or GABAB receptors. However, it is able to efficiently cross the blood brain barrier via an L-system amino acid transporter.
Pregabalin (PGB) is a second generation, more potent, successor to GBP for the treatment of the same conditions as those listed above. GBP (Structure GBP, below) and PGB (Structure PGB, below) bind to the α2δ-1 sub-unit with IC50 values of 140 and 80 nM, respectively (Dolphin (2013) Bioch Biophys Acta 1828: 1541-1549).

GBP shows few, if any, toxic side effects at clinically-relevant doses. It does, however, possess a relatively short half-life, being excreted unchanged, possibly due to very high water solubility and apparent lack of protein binding in vivo. Mild sedation, dizziness and ataxia are the main dose-limiting side effects and these are believed to be centrally-mediated.
GBP and PGB, unlike many other centrally-acting drugs, are hydrophilic and doubly-charged at neutral pH, making them insoluble in lipids, such as cell membranes. However, both compounds appear to cross membrane barriers of the gut, blood-brain barrier and cell membranes via a specialised transporter system (system L) that also transports endogenous amino acids, such as L-leucine, L-isoleucine and L-valine (Su et al (2005) J. Pharm. Exp. Ther. 313, 1-10).
In mammals, there are four related sub-types of the α2 protein, each coded by a different gene. Each protein sub-type has a molecular weight of approximately 150 kiloDaltons (kD) and consists of 997-1150 amino acid residues. Only α2δ sub-types 1 and 2 bind PGB with high affinity; sub-types 3 and 4 are devoid of significant drug binding (Fink et al (2002) Neuropharmacology, 42, 229-236). The binding affinity of PGB is similar for recombinant α2δ type 1 and type 2 proteins, demonstrating that PGB is not sub-type selective (Piechan et al (2004) Soc. Neuroscience Abstr., 111 (program No 115)).
WO 2015/091463 discloses inter alia a bicyclic γ-amino tetrazole derivative of Formula 1,
useful in the treatment of pain, and production methods therefor.
US 2012/0071685 relates to the production of bicyclic γ-amino acid derivatives having activity as a α2 ligand and intermediates thereof, including the synthesis of a diastereomeric mixture of compounds of Formulae 2a, 2b.

However, this diastereoisomeric mixture 2a, 2b is not resolved into individual isomers.
US 2014/0094623 discloses a 3-step method to produce a compound of Formula A and a compound of Formula B from a mixture thereof
by (a) reacting a bis-allylic acetal with an acid or acid anhydride and an acid to produce an aldehyde by Claisen rearrangement, (b) heating the product of stage (a) with malonic acid to produce an alpha-beta unsaturated acid and (c) heating the product of stage (b) with an acid anhydride and a tertiary amine to produce the 4-5 bicyclic ring system by a [2+2] cycloaddition reaction. The separation of above-identified compounds of Formula A or Formula B from a diastereoisomeric mixture thereof is also described in US 2015/0038738, which discloses an enzymatic method to separate the compounds, and in US 2014/0296569, which utilises a reaction of the diastereoisomeric mixture with an acidic benzaldehyde reagent, an optically active amine and a solvent.